Upstream Open Reading Frames as Regulators of mRNA Translation
Open accessAbstract
Continuing discoveries of new and surprising mechanisms of gene regulation suggest that our understanding of this complex and ubiquitous biological process remains incomplete. Emerging examples illustrate that many and perhaps all genes are regulated at multiple steps including transcription, posttranscriptional processing, nuclear export and localization, stability, and translation of mature mRNA molecules. Translation itself is regulated by a diverse collection of mechanisms that act not only at the initiation step but also during elongation and termination and even after termination. Among the various cis elements in mRNAs (43) that participate in regulating translation are AUG codons within transcript leaders (upstream AUGs [uAUGs]) and, in some cases, associated upstream open reading frames (uORFs). Based on a 1987 survey, less than 10 % of eukaryotic mRNAs contain
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Sequences with out-of-frame upstream start codons (uAUGs) or upstream open reading frames (uORFs) show decreased ribosome loading.
“Our data clearly show the expected decrease in ribosome loading for sequences with either out-of-frame upstream start codons (uAUGs) (Fig. 1c) or upstream open reading frames (uORFs) (Supplementary Fig. 2b)18,19.”
From Human 5′ UTR design and variant effect prediction from a massively parallel translation assay (2019) · cites this paper as [18]
In “uORF RECOGNITION BY SCANNING RIBOSOMES” (page unavailable), the review reports that a uORF reduces downstream translation by about tenfold. “NASCENT PEPTIDES MEDIATE REGULATION BY SOME uORFs” explains that ribosomes can still load onto the mRNA but be blocked from reaching the downstream cistron. This supports reduced downstream translation, not a general decrease in ribosome loading for sequences with uORFs or out-of-frame uAUGs. (LLM, conf=0.84)
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- [24]24. Hinnebusch, A. G. 1996. Translational control of GCN4 : gene-specific regulation by phosphorylation of eIF2, p. 199-244. In J. W. B. Hershey, M. B. Mathews, and N. Sonenberg (ed.), Translational control. Cold Spring Harbor Press, Cold Spring Harbor, N.Y.
- [35]35. Lin, F. T., O. A. MacDonald, A. M. Diehl, and M. D. Lane. 1993. A 30-kDa alternative translation product of the CCAAT/enhancer binding protein alpha message: transcription activator lacking antimitotic activity. Proc. Natl. Acad. Sci. USA 90: 9606-9610.
- [43]43. Morris, D. R. 1997. cis -acting mRNA structures in gene-specific translation control, p. 165-180. In J. B. Harford and D. R. Morris (ed.), RNA metabolism and post-transcriptional gene regulation. Wiley-Liss, Inc., New York, N.Y. ing protein messenger RNA is translated into multiple proteins with different
- [44]44. Ossipow, V., P. Descombes, and U. Schibler. 1993. CCAAT/enhancer-bind- transcription activation potentials. Proc. Natl. Acad. Sci. USA 90: 8219-8223.
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- Authors
- Morris, D. R., & Geballe, A. P.
- Affiliations
- University of Washington (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2000-12
- Volume
- 20
- Issue
- 23
- Pages
- 8635-8642
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC86464
- OpenAlex
- W2027195993
- Cited by
- 736
- References
- 0
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 19 · 2023: 21 · 2022: 18 · 2021: 29 · 2020: 34 · 2019: 20 · 2018: 22 · 2017: 22 · 2016: 27 · 2015: 29 · 2014: 24 · 2013: 35 · 2012: 28
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (CA71453, R01CA071453, R01CA039053, CA 39053)
- National Institute of Allergy and Infectious Diseases (AI-26672, R56AI026672, R01AI026672)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- upstream open reading frames, upstream AUGs, mRNA translation regulation, translation initiation, cis-regulatory elements, mRNA stability, post-transcriptional regulation, eukaryotic mRNA
- MeSH terms
- Amino Acid Sequence, Gene Expression Regulation, Models, Genetic, Molecular Sequence Data, Regulatory Sequences, Nucleic Acid, Ribosomes, RNA, Messenger, Protein Biosynthesis, Open Reading Frames
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